Abstract
Background:
The isatuximab, pomalidomide, and dexamethasone (Isa-Pd) regimen has shown survival benefits for relapsed and/or refractory multiple myeloma (RRMM) in several trials, while evidence of effectiveness and safety among Chinese patients is limited. This study aimed to provide real-world evidence of Isa-Pd in Chinese patients with RRMM.
Methods:
In a prospective observational real-world study (IsaFiRsT), we enrolled Chinese RRMM patients who had received ≥2 prior therapies, including lenalidomide and proteasome inhibitors, and received the Isa-Pd regimen at Shanghai Jiaotong University School of Medicine, Ruijin-Hainan Hospital. A historical cohort of patients with RRMM who had received >1 additional line of treatment after ≥2 prior therapies was retrospectively included. The primary endpoint of the Isa-Pd cohort was the overall response rate (ORR). Inverse probability treatment weighting (IPTW) was used to balance confounding factors between the Isa-Pd cohort and historical cohort.
Results:
The Isa-Pd cohort comprised 24 patients with RRMM and reported an ORR of 82.6% (19/23, 95% confidence interval [CI]: 61.2% to 95.0%), a very good partial response or better rate of 73.9% (17/23) and a complete response or better rate of 43.5% (10/23). The median time to first response was 1.2 months (range: 0.9, 3.1 months). The median duration of response, progression-free survival (PFS), and overall survival (OS) were not reached, with a median follow-up of 8.4 months. The 6-month PFS and OS rates were 87.0% and 91.3%, respectively. The IPTW-adjusted ORR in the Isa-Pd cohort was 85.1% compared to 33.4% in the historical cohort, with a risk ratio of 2.55 (95% CI: 1.73 to 4.12). The most common grade >3 treatment-emergent adverse events in the Isa-Pd cohort were neutrophil count decreased (75.0%, 18/24), white blood cell count decreased (54.2%, 13/24), and anemia (45.8%, 11/24).
Conclusion:
The IsaFiRsT study reported that Isa-Pd provided a high rate of deep and rapid response in heavily pretreated Chinese RRMM patients, with an acceptable safety profile in a real-world setting, consistent with Isa-Pd trials.
Registration:
Chinese Clinical Trial Registry (ChiCTR2200062878).
Keywords: Multiple myeloma, Isatuximab, Pomalidomide, Real-world
Introduction
Despite advancements in the therapeutic landscape that have substantially improved prognosis, multiple myeloma (MM) remains incurable.[1] For newly diagnosed MM, the cornerstone of first-line treatment included combinations of proteasome inhibitors (PIs) such as bortezomib and immunomodulatory drugs (IMiDs) such as lenalidomide.[2,3] In China, first-line bortezomib- and lenalidomide-based therapies yield a median progression-free survival (PFS) of approximately 26 months.[4,5] Therapy options for relapsed and/or refractory MM (RRMM) after the use of IMiDs and PIs become notably restricted, particularly after resistance to these agents develops, which is exacerbated by the increasing use of lenalidomide and PIs in front-line settings.[6] The management strategy for RRMM typically involves alternating between different classes of drugs to overcome resistance developed against previous treatments.[7] The prognosis for these double-refractory patients is particularly dismal,[8] underscoring an urgent need for new therapeutic strategies.
The therapeutic landscape for RRMM has been significantly enriched by the introduction of CD38 monoclonal antibodies, which offer a novel therapeutic mechanism distinct from PIs and IMiDs.[9,10] Isatuximab IgG1 monoclonal antibody binds to a specific epitope of CD38 and acts through several mechanisms to kill myeloma cells.[11,12] Clinical trials, notably the ICARIA-MM phase III study,[13] have documented the efficacy of the combination of isatuximab with pomalidomide and dexamethasone (Isa-Pd), demonstrating significant improvement in PFS[13] and overall survival (OS)[14,15] compared to the regimen without isatuximab. Subgroup analyses from ICARIA-MM suggest that Isa-Pd is effective and safe across different ethnic groups, including East Asians.[16] These findings are further supported by real-world studies, such as a retrospective cohort in the UK[17] and another retrospective cohort in France,[18] confirming the regimen’s effectiveness in broader clinical settings. However, evidence is still lacking for Chinese patients with RRMM.
Though not commercially marketed in China, isatuximab has been approved to be incorporated into real-world studies under the auspices of the Hainan Boao Lecheng International Medical Tourism Pilot Zone, a unique policy initiative by the National Medical Products Administration. This prospective observational study aims to evaluate the real-world effectiveness and safety of the Isa-Pd regimen among Chinese patients with RRMM.
Methods
Study design and patients
The IsaFiRsT study (ChiCTR2200062878) was a prospective, real-world observational study conducted at Shanghai Jiaotong University School of Medicine, Ruijin-Hainan Hospital. Eligibility criteria for inclusion were (1) age ≥18 years, (2) a confirmed diagnosis of MM with a history of at least two prior therapies including lenalidomide and a PI, (3) presence of measurable disease at baseline, defined as a serum M-protein concentration of >0.5 g/dL or a urine M-protein level of >200 mg/24 hours, and (4) planned treatment with the Isa-Pd regimen based on physicians’ decisions. Patients were excluded if they (1) had previously been treated with any CD38 monoclonal antibodies, (2) exhibited severe hypersensitivity to isatuximab or any of its components, (3) were pregnant, (4) were deemed by their physician to be unable to tolerate any component of the Isa-Pd regimen, or (5) were concurrently enrolled in another clinical trial that specified treatments or disease management protocols for MM.
This study incorporated a historical cohort that included adult patients with RRMM, retrospectively extracted from 10 tertiary level-A hospitals all over China from January 1, 2018, to December 31, 2020. Eligibility criteria for this cohort included adults with RRMM who had received at least two prior therapies, including lenalidomide and a PI, followed by at least one additional line of anti-myeloma treatment subsequent to these therapies. All data of the historical cohort relevant to the study were collected from the electronic medical records.
Ethical approval for this study was approved by the Ethics Committee of Shanghai Jiaotong University School of Medicine, Ruijin-Hainan Hospital (No. 2022-022). Written informed consent was obtained from all patients in the Isa-Pd cohort. For the historical cohort, the requirement for informed consent was signed by the patient or waived by the ethics committee due to its retrospective nature.
Treatment regimen
The label-recommended dosing for isatuximab was 10 mg/kg weekly during the first 4-week cycle (days 1, 8, 15, and 22) and biweekly (days 1 and 15) for the second and subsequent cycles. Pomalidomide was recommended at a dose of 4 mg daily orally from days 1 to 21 of each cycle. Dexamethasone was recommended to be administered orally or intravenously 40 mg (20 mg if aged >75 years) weekly on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, treating physician’s decision, patient wish, or any other reason. The Isa-Pd treatment regimen could be adjusted based on the clinical judgment of the treating physicians.
Follow-up and outcomes
The Isa-Pd cohort was followed from the initiation of isatuximab treatment through 30 days after the last administration of the treatment regimen or before the start of further anti-myeloma therapy, whichever comes first. Treatment discontinuation was defined as the cessation of all three drugs: isatuximab, pomalidomide, and dexamethasone.
The primary effectiveness endpoint for the Isa-Pd cohort was the overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), evaluated according to the International Myeloma Working Group (IMWG) criteria by the study investigators. Secondary endpoints included PFS, OS, duration of response (DOR), time to response (TTR), and safety. Adverse events (AEs) were recorded and graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The adverse events of special interest (AESIs) included infusion reactions (IRs), pregnancy, a symptomatic overdose of isatuximab, second primary malignancies, and grade ≥3 neutropenia.
Other effectiveness assessments included the rate of VGPR or better, clinical benefit rate (CBR), which was defined as at least minimal response (MR) or better, minimal residual disease (MRD) negativity rate. MRD was assessed by flow cytometry with a sensitivity threshold of 10−4. For the historical cohort, assessed outcomes included ORR, PFS, and OS.
Statistical analysis
All effectiveness analyses were done in the evaluable population, defined as patients with measurable disease at baseline taking at least one dose of isatuximab and having a valid post-baseline disease evaluation. For the primary endpoint of ORR, to integrate insights from the global ICARIA-MM study, where the ORR for 154 patients under the Isa-Pd regimen was 60% (95% confidence interval [CI]: 52% to 68%),[13] a bridging concept using a Bayesian framework was used. The decision rule, as outlined by Gandhi et al[19], used a beta distribution (parameters 15, 10) informed by the ICARIA-MM data. Based on a meta-analysis of two published studies[20,21] and one registered study (CTR20171397), a clinically meaningful threshold for ORR was set at 41%, which is the upper bound of the 95% CI of ORR through the meta-analysis of these three studies. Under the criteria that the posterior probability of ORR greater than the stated clinical meaningful threshold needs to be larger than 0.9, with 22 effectiveness evaluable patients, the study outcome would be considered positive if nine or more responses were observed. This sample size was expected to yield an 86% probability of success, assuming a true ORR of 50%. The total sample size was increased to 24 treated patients to account for a potential 10% of non-evaluability.
Statistical analyses were conducted using SAS software, version 9.4 (SAS Institute Inc., Cary, North Carolina, United States). ORR, rates of VGPR or better, and CBR were summarized, with their CIs calculated using the Clopper–Pearson exact method. The Kaplan–Meier method estimated time-to-event endpoints, including PFS, OS, and DoR, along with their 95% CIs. TTR was summarized descriptively. Additional analysis was conducted to evaluate the difference in ORR between Isa-Pd and the historical cohort. An inverse probability of treatment weighting (IPTW) method was applied to control for confounding between the Isa-Pd and historical cohorts.[22] The propensity scores were estimated based on the baseline covariates of age (years), MM subtype at study entry (IgG vs. Non-IgG), number of prior lines, and baseline serum creatinine (normal vs. abnormal).
Results
Characteristics of patients in the Isa-Pd cohort
The Isa-Pd cohort enrolled 24 patients with RRMM from September 13, 2022, to May 12, 2023. The median age was 61.5 years (range: 45.0–78.0 years), with 41.7% (10/24) of patients >65 years. The majority (83.3%, 20/24) had an Eastern Cooperative Oncology Group (ECOG) performance score of 1. The median number of previous lines of treatment was 3 (range: 1, 11), with 22 patients (91.7%) refractory to the last regimen. All patients had previously received PIs and IMiDs, with 66.7% (16/24) having been treated with alkylating agents and 20.8% (5/24) with anthracyclines. Two patients (8.3%) previously received pomalidomide. The majority of the cohort was refractory to lenalidomide (95.8%, 23/24), PIs (91.7%, 22/24), or both (91.7%, 22/24) [Table 1].
Table 1.
Baseline characteristics of the Isa-Pd cohort.
| Variables | Isa-Pd cohort (n = 24) |
|---|---|
| Age (years), median (range) | 61.5 (45.0, 78.0) |
| <65 years, n (%) | 14 (58.3) |
| 65–75 years, n (%) | 9 (37.5) |
| >75 years, n (%) | 1 (4.2) |
| Sex, n (%) | |
| Male | 11 (45.8) |
| Female | 13 (54.2) |
| ECOG score, n (%) | |
| 0 | 0 |
| 1 | 20 (83.3) |
| 2 | 0 |
| Missing | 4 (16.7) |
| ISS stage at initial diagnosis, n (%) | |
| I | 1 (4.2) |
| II | 5 (20.8) |
| III | 8 (33.3) |
| Unknown | 10 (41.7) |
| R-ISS stage at initial diagnosis, n (%) | |
| I | 0 |
| II | 3 (12.5) |
| III | 4 (16.7) |
| Unknown | 17 (70.8) |
| Type of MM at diagnosis, n (%) | |
| IgA | 6 (25.0) |
| IgG | 12 (50.0) |
| IgD | 3 (12.5) |
| Light chain | 3 (12.5) |
| ISS stage at study entry, n (%) | |
| I | 6 (25.0) |
| II | 2 (8.3) |
| III | 4 (16.7) |
| Unknown | 12 (50.0) |
| R-ISS stage at study entry, n (%) | |
| I | 0 |
| II | 2 (8.3) |
| III | 2 (8.3) |
| Not classified | 20 (83.3) |
| Time from initial diagnosis of MM to first dose of isatuximab treatment (year), median (range) | 2.8 (1.1, 8.0) |
| ≤5 years, n (%) | 20 (83.3) |
| >5 years, n (%) | 4 (16.7) |
| Previous lines of treatment, median (range) | 3 (1, 11) |
| Prior therapy, n (%) | |
| PI | 24 (100) |
| Immunomodulators | 24 (100) |
| Alkylating agents | 16 (66.7) |
| Anthracyclines | 5 (20.8) |
| CAR-T cell therapy | 1 (4.2) |
| Refractory to previous therapy, n (%) | |
| Lenalidomide | 23 (95.8) |
| PI | 22 (91.7) |
| Lenalidomide and PI | 22 (91.7) |
| Last line of therapy | 22 (91.7) |
| Prior transplantation, n (%) | 5 (20.8) |
| Prior tandem transplantation, n (%) | 2 (8.3) |
| Time from last transplant to first dose of isatuximab treatment (months), median (range) (n = 5) | 23 (8, 49) |
CAR-T: Chimeric antigen receptor T-cell therapy; ECOG: Eastern Cooperative Oncology Group; IgA: Immunoglobulin A; IgG: Immunoglobulin G; IgD: Immunoglobulin D; Isa-Pd: Isatuximab with pomalidomide and dexamethasone; ISS: International Staging System; MM: Multiple myeloma; PI: Proteasome inhibitor; R-ISS: Revised International Staging System.
As of the data cutoff date on November 12, 2023, 79.2% (n = 19) remained on treatment. Treatment discontinuation was attributed to progressive disease in 12.5% (n = 3) and to AEs in 8.3% (n = 2). The median number of treatment cycles completed was 7 (range: 1, 10), with the median duration of exposure being 30.5 weeks (range: 1.6, 59.1 weeks).
Treatment response with Isa-Pd regimen
In the Isa-Pd cohort, 23 patients provided evaluable response data, as depicted in Figure 1. The ORR assessed by investigators was 82.6% (n = 19), including 7 (30.4%) sCR, 3 (13.0%) CR, 7 (30.4%) VGPR, and 2 (8.7%) PR. Notably, responses qualifying as CR or better were seen in 10 patients (43.5%), and VGPR or better was achieved in 17 patients (73.9%). The CBR was achieved by 19 patients (82.6%) [Table 2].
Figure 1.
Treatment response in the Isa-Pd cohort. CR: Complete response; Isa-Pd: Isatuximab with pomalidomide and dexamethasone; MR: Minimal response; PD: Progressive disease; PR: Partial response; sCR: Stringent complete response; SD: Stable disease; VGPR: Very good partial response.
Table 2.
Effectiveness among evaluable patients in the Isa-Pd cohort.
| Outcomes | Isa-Pd cohort (n = 23) |
|---|---|
| Best overall response, n (%) | |
| Stringent complete response | 7 (30.4) |
| Complete response | 3 (13.0) |
| Very good partial response | 7 (30.4) |
| Partial response | 2 (8.7) |
| Minimal response | 0 |
| Stable disease | 4 (17.4) |
| Progressive disease | 0 |
| Overall response, n (%) | 19 (82.6) |
| 95% CI, % | 61.2 to 95.0 |
| Very good partial response or better, n (%) | 17 (73.9) |
| 95% CI, % | 51.6 to 89.8 |
| Clinical benefit rate, n (%) | 19 (82.6) |
| 95% CI, % | 61.2 to 95.0 |
CI: Confidence interval; Isa-Pd: Isatuximab with pomalidomide and dexamethasone.
No disease progression or death was observed among responders as of the data cutoff date, and the median DOR was not reached. The median time to first response was 1.2 months (range: 0.9 to 3.1 months). The MRD negativity rate was 65.2% (15 out of 23 evaluable patients), with a median time to first MRD negativity recorded at 85.0 days (range: 29.0 to 169.0 days).
Survival in the Isa-Pd cohort
With a median follow-up time of 8.41 months for the Isa-Pd cohort, the median PFS was not reached with 2 (8.7%) cases of disease progression and 2 (8.7%) deaths. The estimated 6-month PFS rate was 87.0% (95% CI: 64.8% to 95.6%) [Figure 2]. The median OS also was not reached (95% CI: NE to NE) with a 6-month OS rate of 91.3% (95% CI: 69.5% to 97.8%).
Figure 2.
Kaplan–Meier curves of progression-free survival in the Isa-Pd cohort. Isa-Pd: Isatuximab with pomalidomide and dexamethasone.
Safety of the Isa-Pd regimen
In the Isa-Pd cohort, all patients experienced at least one treatment-emergent adverse event (TEAE) of any grade, with an incidence of 95.8% for grade ≥3 TEAEs [Table 3]. The most frequently observed grade ≥3 TEAEs (incidence >10%) included decreased neutrophil count (75.0%, 18/24), decreased white blood cell count (54.2%, 13/24), anemia (45.8%, 11/24), decreased platelet count (37.5%, 9/24), pneumonia (29.2%, 7/24), and hypokalemia (12.5%, 3/24) [Table 4]. Nineteen patients (79.2%) experienced serious adverse events (SAEs). The most commonly reported SAEs (incidence >5%) were decreased neutrophil count (41.7%, 10/24), pneumonia (25.0%, 6/24), decreased platelet count (20.8%), COVID-19 pneumonia (12.5%, 3/24), infection (8.3%, 2/24), and anemia (8.3%, 2/24). Two (8.3%, 2/24) patients discontinued treatment permanently due to TEAEs, including 1 (4.2%, 1/24) fatal TEAE (death with unknown reason).
Table 3.
Summary of safety in the Isa-Pd cohort.
| Events | Isa-Pd cohort (n = 24) |
|---|---|
| Any grade TEAE | 24 (100) |
| Grade >3 TEAE | 23 (95.8) |
| TEAE leading to treatment discontinuation | 2 (8.3) |
| SAE | 19 (79.2) |
| TRSAE | 16 (66.7) |
| Isatuximab-related SAE | 13 (54.2) |
| TEAE leading to death | 1 (4.2) |
| AESI | 21 (87.5) |
| TRAE | 24 (100) |
| Isatuximab-related TRAE | 24 (100) |
| Grade >3 TRAE | 22 (91.7) |
| Grade >3 isatuximab-related TRAE | 22 (91.7) |
Data are expressed as n (%). AESI: Adverse events of special interest; Isa-Pd: Isatuximab with pomalidomide and dexamethasone; SAE: Serious adverse events; TEAE: Treatment-emergent adverse events; TRAE: Treatment-related adverse events; TRSAE: Treatment-related serious adverse events.
Table 4.
The most common treatment-emergent adverse events (incidence of any grade >20%) and hematological laboratory abnormalities in the Isa-Pd cohort.
| Events | Any grade (n = 24) | Grade >3 (n = 24) |
|---|---|---|
| TEAEs | ||
| Pneumonia | 10 (41.7) | 7 (29.2) |
| Anemia | 23 (95.8) | 11 (45.8) |
| Hypoproteinemia | 21 (87.5) | 0 |
| Hypokalemia | 15 (62.5) | 3 (12.5) |
| Hypocalcemia | 8 (33.3) | 0 |
| Constipation | 11 (45.8) | 0 |
| Diarrhea | 8 (33.3) | 0 |
| Abnormal hepatic function | 13 (54.2) | 1 (4.2) |
| Pruritus | 8 (33.3) | 0 |
| Influenza-like illness | 5 (20.8) | 0 |
| Decreased neutrophil count | 24 (100) | 18 (75.0) |
| Decreased white blood cell count | 24 (100) | 13 (54.2) |
| Decreased platelet count | 17 (70.8) | 9 (37.5) |
| Decreased weight | 5 (20.8) | 0 |
| Infusion-related reaction | 10 (41.7) | 1 (4.2) |
| Hematological laboratory abnormalities (worst grade in evaluable patients) | ||
| Neutropenia | 24 (100) | 19 (79.2) |
| Thrombocytopenia | 23 (95.8) | 9 (37.5) |
| Anemia | 24 (100) | 13 (54.2) |
Data are expressed as n (%). Isa-Pd: Isatuximab with pomalidomide and dexamethasone; TEAE: Treatment-emergent adverse events.
Isatuximab IRs were reported in 41.7% of patients (n = 10), with only one grade 3 case (4.2%) leading to isatuximab permanent discontinuation. The onset of the IRs occurred during infusion day, and all of them were resolved within 1 day. The most common symptoms associated with IRs, occurring in more than 5% of cases, were chest discomfort (25.0%, 6/24), dyspnea (12.5%, 3/24), and symptoms including cough, chills, and pyrexia (8.3%, 2/24 each).
Historical cohort
The external historical cohort included 230 patients. This cohort had a diverse treatment history, with a median of 4 prior regimens (range: 1 to 20) and a median of 2 prior lines of therapy (range: 1 to 10).
Of these 230 patients, 74 were evaluable for treatment response, with an ORR of 31.1% (95% CI: 20.8% to 42.9%). Among these, 61 patients without missing covariates were included in the comparison of ORR with the Isa-Pd cohort following the application of IPTW [Supplementary Table 1, http://links.lww.com/CM9/C469]. The most common therapies among these patients were corticosteroids (91.8%, 56/61), PIs (68.9%, 42/61), IMiDs (49.2%, 30/61), and alkylating agents (41.0%, 25/61). Twelve patients (19.7%) had received anti-CD38 therapies, and three patients (4.9%) received chimeric antigen receptor cell therapy (4.9%). Post-IPTW, the ORR for the Isa-Pd cohort was 85.1% compared to 33.4% in the historical cohort, with a risk ratio of 2.55 (95% CI: 1.73 to 4.12).
Among 205 patients available for PFS analysis, 60 events were observed, yielding a median PFS of 10.02 months (95% CI: 6.67 to 12.12 months). For OS data from 224 patients, only eight deaths (3.6%) were reported, and the median OS was not reached.
Discussion
At the time of the IsaFiRsT study initiation in 2022, there was no clinical study or real-world study of the Isa-Pd regimen on Chinese patients with RRMM. The IsaFiRsT study was a real-world study that investigated the Isa-Pd regimen within the Chinese RRMM patient population, providing evidence of its effectiveness and safety. Our findings reported a substantial ORR of 82.6% with the Isa-Pd regimen, comparable to those reported in clinical trials.[13] Importantly, responses qualifying as CR or better were seen in 43.5% of patients and VGPR or better in 73.9%, with an MRD negativity rate at sensitivity level 10−4 of 65.2%. The median time to first response was 1.2 months, and the median DOR was not reached, suggesting a rapid, high, deep, and durable response. Survival outcomes were promising, with a 6-month PFS and OS rates of 87.0% and 91.3%, respectively. The treatment was well tolerated, with manageable AEs. This study fills the gap in knowledge regarding the use of the newer therapeutic option of isatuximab in Chinese RRMM populations, which supported the integration of Isa-Pd into the therapeutic arsenal for RRMM in China.
Previous phase II trials and real-world studies in the Chinese population reported ORRs ranged 37.8–57.8% in RRMM with pomalidomide and dexamethasone across patients with diverse characteristics, including lenalidomide-refractory patients, patients with high-risk cytogenetics, and patients with kidney impairment.[23–26] The IsaFiRsT study consistently demonstrates the addition of isatuximab to pomalidomide-dexamethasone significantly improves the treatment effectiveness in the target population in Chinese population compared with the global. As reported in pivotal studies such as the ICARIA-MM trial,[13] the Isa-Pd regimen achieved an ORR of 60% and a rate of VGPR or above of 32%,[13] which were similar with those reported in the APOLLO study with subcutaneous daratumumab plus pomalidomide and dexamethasone.[27] In the present Chinese RRMM cohort, the ORR reached 82.6%, and the rate of VGPR or better was 73.9%, which aligns closely with the response observed in the East Asian subgroup of the ICARIA-MM study, where the ORR was 71.4% and the rate of VGPR or better was 61.9%.[16] The numerically higher ORR in the present study compared to those reported in the ICARIA-MM trial might be attributed to the small sample size here and baseline characteristics specific to our study population. For instance, the present cohort had a slightly younger median age (62 years) compared to 68 years in the ICARIA-MM trial.[13] However, our results on median age are comparable to those reported in publications on Chinese RRMM,[28] suggesting the generalizability of the study population. In addition, the ORR in the present study was comparable to that in a UK real-world cohort (66.4%).[17] Nevertheless, in the French IMAGE study, the real-world ORR was 46.3%, with only 27.9% achieving VGPR or better,[18] which might exhibit a potential variation in the study population (e.g., prior exposure to anti-CD38 therapies). Overall, the reported ORR in our cohort reflected the real-world effectiveness of the Isa-Pd regimen in RRMM, which was consistent with those in clinical trials and supported by a relatively high rate of CR/sCR.
Regarding long-term outcomes, our study reported not yet reaching the median PFS and OS, with 6-month PFS rates of 87.0% and 6-month OS rates of 91.3%, respectively. These results suggest a substantial translation of initial, deep response into survival benefits, which echoes the results from the ICARIA-MM trial[13] and real-world data from the UK and French studies.[17,18] Considering the limited follow-up period in our study, further observation will be required to confirm these promising outcomes as comprehensive real-world evidence.
In the present studies, a historical cohort was included to be compared with the Isa-Pd cohort. Specifically, the ORR post-IPTW for the Isa-Pd cohort was remarkably high at 85.1%, and the ORR was 33.4% in the historical cohort, translating into a risk ratio of 2.55 (95% CI: 1.73–4.12). However, this comparison may be affected by the inherent limitations associated with missing data in the external controls, which could introduce selection bias, thus potentially overstating the effectiveness observed in the Isa-Pd cohort. Notwithstanding these concerns, the ORR achieved by the historical cohort aligns closely with the outcomes reported in other real-world RRMM studies conducted in China.[29–31] Nevertheless, the high proportion of censored data early after treatment and insufficient record of progression or death events reminds us to interpret the results of PFS and OS in the historical cohort with caution. Overall, these data presented the effectiveness of Isa-Pd in a real-world setting, suggesting that this regimen could offer a therapeutic advantage for RRMM patients.
In this study, the safety profile observed was similar to that reported in other studies, including the ICARIA-MM trial and various real-world analyses, reinforcing the regimen’s manageability in clinical practice. For instance, in the ICARIA-MM trial, IR specific to the isatuximab combination was documented but was manageable; only 3% of patients experienced grade 3 or 4 reversible IR.[13] It is mirrored in our findings where only one case (4.2%) had grade 3 IR. Moreover, during the on-treatment period, grade 3 or 4 laboratory neutropenia was reported in 79.2% of patients, which is consistent with that in the ICARIA-MM trial (84.8%).[13] Like our study, with no increase in treatment discontinuations or incidence of fatal events, the French IMAGE study also reflected a manageable safety profile, with no new safety signals emerging and only 1.3% of patients discontinuing treatment due to AEs, highlighting the regimen’s tolerability.[18] Overall, these findings showed that the adverse events of Isa-Pd were expected and manageable, fitting within the established safety profiles reported in other clinical and real-world settings.
Our study has some limitations that need to be considered. First, the limited sample size of our study might limit the generalizability of our findings. However, this study aimed to integrate insights from the global ICARIA-MM study through a bridging concept using a Bayesian framework. The probability of success was ensured based on the sample size calculation. Second, the short follow-up period constitutes another limitation. Last, using an external historical cohort poses inherent challenges. This non-parallel control lacks contemporaneity but exhibits patient characteristics and treatment patterns of Chinese RRMM in clinical practice. These limitations highlight the importance of further studies with larger sample sizes and longer follow-up periods.
In conclusion, the isatuximab, pomalidomide, and dexamethasone regimen showed a high, deep, and rapid therapeutic response among heavily pretreated Chinese patients with RRMM, with a known and manageable safety profile. These findings not only reinforce the real-world applicability of Isa-Pd in a Chinese clinical setting but also align with the results observed in the ICARIA-MM study, supporting the integration of Isa-Pd for the treatment of RRMM in China.
Acknowledgements
We acknowledge the valuable contributions of all members and sites in this clinical trial. Editorial support for the manuscript was provided by Dr. Fabao Zhang of Shanghai MedSci Technology Co., Ltd.
Conflicts of interest
This study was sponsored by Sanofi Pharmaceuticals. Feng ZY, Zhou L, Wang ZN, Shen D, and Liu G are employees of Sanofi and may hold shares and/or stock options in the company. We thank the Sanofi Study Team for participating in the study design and coordinating the study conduction process. We thank the Sanofi Medical Team for providing statistical advice and assistance with writing.
Supplementary Material
Footnotes
Wenting Chen, Jianhua You, Li’e Lin, and Xiaojing Yan contributed equally to this work.
How to cite this article: Chen WT, You JH, Lin LE, Yan XJ, An G, Wang YF, Tian WW, Ding KY, Zhang X, Chen WM, Wang YX, Fang BJ, Liu J, Xia WL, Feng ZY, Zhou L, Wang ZN, Shen D, Liu G, Zhao WL. Real-world outcomes of isatuximab with pomalidomide and dexamethasone for relapsed and/or refractory multiple myeloma. Chin Med J 2026;139:589–596. doi: 10.1097/CM9.0000000000003649
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